Patients with severe neurological dysfunction such as motor deficits (e.g. cerebral palsy, peripheral neuromuscular disease, facial paralysis, Parkinson's disease, severe mental retardation, and other conditions such as stroke and esophageal cancer) suffer from sialorrhoea (or drooling), which is the unintentional loss of saliva and other oral contents from the mouth. Drooling is often found in individuals with neurological dysfunction. For example, socially significant drooling occurs in approximately 10% of patients with cerebral palsy. Persistent drooling beyond the ages of 3 or 4 years is considered abnormal drooling. Sialorrhoea results from either a hypersecretion of saliva or an impaired ability to swallow; the latter is a particular problem in patients with motor dysfunction.
Drooling causes impairment of speech, feeding and swallowing problems and aspiration. Control of drooling is important in preventing choking and gagging in persons with posterior drooling. Persons who are motor-impaired can use the many new electronic assistance aids to communicate, navigate and provide more integration and self-sufficiency in everyday life. Unfortunately for those who drool, many of the aids are controlled through the mouth or facial manipulations. The drooling may cause social isolation and inability to use the new devices.
Not only is the drooling annoying and limiting for the person with sialorrhoea, there are problems for the caregivers. Carers must clean and control the drooling, and remove the drool from the body, clothes and surrounding equipment of the drooler. Additionally, carers must be very careful about exposure to bodily fluids such as drool.
Thus, it is recognized that sialorrhoea requires medical attention. Current treatment includes administration of anticholinergic agents such as glycopyrrolate and scopolamine, botulinum toxin injections and surgery.
Where an anti-sialorrheic effect (reduced saliva secretion) is required, it is appropriate neither to completely impair secretion nor to prevent saliva production in response to food etc. It may be possible to reduce the amount of saliva produced by administering an anticholinergic agent, as demonstrated by the positive effects of glycopyrrolate (tablets) and scopolamine (dermal patch). Although glycopyrrolate is a quaternary ammonium compound with restricted access to the CNS, it is not well tolerated by around 20-25% of patients. Likewise, scopolamine is reasonably tolerated for a few days, but many systemic side-effects are encountered. The saliva produced following administration of glycopyrrolate or scopolamine is extremely thick and as such is unpleasant.
Clonidine is an α2-adrenoceptor agonist and is primarily used clinically as an antihypertensive agent. It acts within the central nervous system to reduce sympathetic nervous tone to the periphery. Besides lowering blood pressure and heart rate, clonidine also causes pronounced sedation and dry mouth. Clonidine has been shown to be effective in reducing sialorrhoea induced by clozapine (Grabowski, 1992, J. Clin. Psychopharmacol., 12, 69-70; Praharaj et al., 2005, J. Psychopharmacol., 19, 426-428). Clonidine (0.15 mg) has been given per os to 17 Parkinson's patients and found to significantly reduce sialorrhoea. Four of the 17 patients experienced side-effects.
Clonidine is one of many imidazole-type compounds that are used clinically to treat conditions such as hypertension, sedation as an adjunct to anaesthesia (premedication), muscle spasm (spasticity), and withdrawal symptoms of opiate and alcohol abuse. Examples of other such compounds are rilmenidine, dexmedetomidine, tizanidine, moxonidine and lofexidine. All produce their clinical effects by stimulating α2-adrenoceptors in the brain and cause sedative side-effects and dry mouth.
Sialorrhoea can be a side-effect of the administration of certain drugs. For example, clozapine-induced sialorrhoea has been treated with some success with solutions of the non-selective muscarinic receptor antagonist ipratropium, a quaternary derivative of atropine, given either sublingually or intranasally (O. Freudenreich et al., 2004, J. Clin. Psychopharmacol., 24, 98-100; J. Calderon et al., 2000, Int. Clin. Psychopharmacol., 15, 49-52). Freudenreich et al. (2004) gave ipratropium nasal spray (0.03-0.06%) sublingually to 8 patients receiving clozapine and who suffered from excessive drooling. After several weeks of use, a full response was reported in 2 patients and a partial response (symptoms controlled for 2-8 hours) in 5 patients, while 1 patient was a non-responder. One drawback with the ipratropium solution is its bitter taste. In addition, an ophthalmic solution of atropine given sublingually was found to reduce clozapine-indiced sialorrhoea (A. Sharma et al., 2004, Ann. Pharmacother., 38, 1538). In a small case study, ophthalmic atropine solution was given sublingually to patients with Parkinson's disease and significant decline in saliva production was recorded. However, 2 of the 7 patients suffered hallucinations (H. C. Hyson et al., 2002, Mov. Disorders, 17, 1318-1320). Atropine is a non-selective muscarinic antagonist that exhibits significant central nervous system side-effects. The use of non-selective muscarinic antagonists that extensively enter the brain and produce undesirable side-effects should be avoided, particularly in patients with Parkinson's disease (PD).
Another class of known drugs is of anti-muscarinic agents. A new generation of anticholinergic muscarinic antagonists is being developed for indications such as urinary incontinence, overactive bladder, irritable bowel syndrome or COPD. These compounds include tolterodine, darifenacin, solifenacin, zamifenacin, Ro-3202904 (PSD-506), oxybutynin, trospium, revatropate and tiotropium.
Patients with PD are more prone to confusion and hallucinations, particularly as their disease progresses. Also their blood-brain barrier may become more leaky. They are thus much more prone to worsening confusion and hallucinations when given an anticholinergic agent. Sleep problems are also extremely common in PD. α2 agonists promote sleep and therefore are undesirable in PD. Furthermore, in the more elderly population, cardiovascular problems are much more common, as is, particularly in males, bladder outflow obstruction. α2 agonists would be undesirable for the former and anti-muscarinic agents for both.